A genetic variation in microRNA target site of ETS2 is associated with clinical outcomes of paclitaxel-cisplatin chemotherapy in non-small cell lung cancer.

Mi Jeong Hong,Cheng Cheng Jin,Kyung Min Shin,So Yeon Lee,Jaehee Lee,Ji Yun Jeong,Won Kee Lee,Ji Woong Son,Chang Ho Kim,Hyo Jung Kang,Jin Eun Choi,Shin Yup Lee,Seung Ick Cha,Sun Ah Baek,Seung Soo Yoo,Jae Yong Park

doi:10.18632/oncotarget.7433

Abstract

The present study was performed to investigate the association of single nucleotide polymorphisms (SNPs) located in the miRNA target sites with the clinical outcomes of first line paclitaxel-cisplatin chemotherapy in advanced NSCLC. Eighty SNPs in miRNA binding sites of cancer related genes selected from 18,500 miRNA:target bindings in crosslinking, ligation, and sequencing of hybrids (CLASH) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry-based genotype assay. qRT-PCR and luciferase assay were conducted to examine functional relevance of potentially functional SNPs in miRNA binding sites. Of the 80 SNPs analyzed, 16 SNPs were significantly associated with the clinical outcomes after chemotherapy. Among these, ANAPC1 rs3814026C>T, ETS2 rs461155A>G, SORBS1 rs7081076C>A and POLR2A rs2071504C>T could predict both chemotherapy response and survival. Notably, ETS2 rs461155A>G was significantly associated with decreased ETS2 mRNA expression in both tumor and paired normal lung tissues (Ptrend = 4 × 10−7, and 3 × 10−4, respectively). Consistently, a decreased expression of the reporter gene for the G allele of rs461155 compared with the A allele was observed by luciferase assay. These findings suggest that the four SNPs, especially ETS2 rs461155A>G, could be used as biomarkers predicting the clinical outcomes of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.

Highlights

MicroRNAs are endogenous small (~22 nucleotides) non-coding RNAs that repress target gene expression by complementary binding to the 3’-untranslated region (3’-UTR) of messenger RNAs, leading to translational repression or mRNA cleavage [1, 2]
These findings suggest that the four single nucleotide polymorphisms (SNPs), especially ETS2 rs461155A>G, could be used as biomarkers predicting the clinical outcomes of non-small cell lung cancer (NSCLC) patients treated with first-line paclitaxel-cisplatin chemotherapy
We investigated the associations between SNPs in miRNA target sites and the treatment outcomes of 1st line paclitaxel-cisplatin chemotherapy, to identify genetic variations that affect the clinical outcomes in NSCLC

Summary

Introduction

MicroRNAs (miRNAs) are endogenous small (~22 nucleotides) non-coding RNAs that repress target gene expression by complementary binding to the 3’-untranslated region (3’-UTR) of messenger RNAs (mRNAs), leading to translational repression or mRNA cleavage [1, 2]. Many studies have suggested that single nucleotide polymorphisms (SNPs) in miRNA target sites are associated with the risk and the prognosis of diverse types of cancer, including lung cancer [9,10,11,12]. Most of the studies investigated miRNA binding sites identified by computational prediction methods such as miRanda and TargetScan [13,14,15]. Those were developed to predict miRNA-mRNA binding based primarily on the complementarity to seed sequence, being biased towards canonical seed pairings at 3’ UTR, and may have frequent false prediction [13,14,15]. Crosslinking, ligation, and sequencing of hybrids (CLASH) provided direct experimental observation of transcriptome-wide miRNAtarget pairs, revealing that the interactions occurred more frequently in coding sequence than 3’ UTR and the majority of miRNA-target bindings were noncanonical [13]

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Results

Conclusion